Streptococcus pneumoniae is a Gram-positive, encapsulated bacterium that is a main cause of infections of the respiratory tract and can lead to severe invasive pneumococcal disease (IPD). More than 90 different pneumococcal serotypes have been described to date. These are classified by the structure of their capsular polysaccharide (CPS), which is unique to each serotype. Consequently, the immune response generated against the CPS varies between different serotypes. This is used to generate specific antibodies in rabbits against the antigen of each serotype. Cross-reactivity between these specific antibodies and other serotypes than those they were raised against is often observed, due to structural similarities of the CPS of different serotypes. Due to its immunological properties, CPS is used as the main component of S. pneumoniae vaccines.
The first efficient vaccine that contained the CPS of four different serotypes was described in 1945. It then took over thirty years until a vaccine was introduced that covered 14 serotypes, shortly followed by a 23-valent vaccine. However, these polysaccharide vaccines had several shortcomings. They were not able to elicit a long-lasting protection and were not effective in the populations most vulnerable to infection, namely children under two years of age, as well as immunodeficient and elderly patients. These shortcomings result from the immunology of carbohydrates and were overcome by the introduction of carbohydrate-protein conjugate vaccines. The first pneumococcal conjugate vaccines were the seven-valent (PCV-7) and 10-valent (PCV-10) vaccine. PCV-7 was later replaced with the most recent vaccine (PCV-13), which contains the CPS-glycoconjugates of 13 different serotypes.
Streptococcus pneumoniae serotype 4 CPS is included in all pneumococcal conjugate vaccines. The SP4 CPS consists of a tetrasaccharide repeating unit with the sequence β-(1,3)-ManNAc-α-(1,3)-FucNAc-α-(1,3)-GalNAc-α-(1,4)-Gal containing an acid labile trans-2, 3 (S)-pyruvate on the galactose moiety (see FIG. 1). Trans-pyruvate ketals are labile to hydrolysis and therefore, are inducing micro heterogeneities to the saccharides isolated from bacterial sources that are intended for vaccinations. Hence, the labile nature of the pyruvate moiety has enormous implications on the structure of the saccharides isolated from S. pneumoniae type 4 bacterial sources and therefore, impacts on the production and stability of the conjugate comprising said saccharides. Structural heterogeneities are detrimental, when considering the trend of vaccine development going in the direction of well-defined subunit vaccines.
It is the objective of the present invention to provide well-defined synthetic saccharides of general formula (I) that are related to Streptococcus pneumoniae serotype 4 capsular polysaccharides. Said saccharides are suitable to be conjugated to an immunogenic carrier to provide conjugates and pharmaceutical composition thereof that are useful for prevention and/or treatment of diseases associated with Streptococcus pneumonia, and more specifically of diseases associated with Streptococcus pneumoniae serotype 4. Furthermore, the synthetic saccharides of general formula (I) are useful as marker in immunological assays for detection of antibodies against Streptococcus pneumoniae bacteria.
The objective of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the figures, and the examples of the present application.